Abstract |
An important site of cellular damage in bacterial sepsis is mitochondrial DNA ( mtDNA), which we proposed is caused by reactive oxygen and nitrogen species generated by activation of signaling through specific toll-like receptors (TLR). In wild-type (Wt) mice injected with heat-inactivated E. coli, hepatic TLR4 and TLR2 proteins were up-regulated with TLR-dependent increases in transcript levels for tumor necrosis factor ( TNF-alpha), interleukin 6, nitric oxide synthase-II (iNOS), and NADPH oxidase 2 (Nox2). The accompanying stress significantly depleted hepatic mtDNA despite eight- and fourfold increases in manganese superoxide dismutase (MnSOD) and mitochondrial transcription factor A (Tfam) expression, respectively. The identical E. coli dose generated significantly less TNF-alpha, NO, and Nox2 in TLR4-/- and TLR2/4-/- but not in TLR2-/- mice. TLR4-/- and TLR2/4-/- compared with Wt mice were protected from mtDNA oxidation but showed no Tfam up-regulation and little copy number restoration. A critical role in the mtDNA damage was determined for TLR4-mediated iNOS transcription through the MyD88 pathway. In Wt mice, mtDNA depletion was avoided by selective iNOS blockade, and residual mtDNA loss was linked to NF-kappaB-dependent TNF-alpha expression. These data disclose the dual role of TLR4 in mtDNA damage and compensatory mitochondrial biogenic responses after innate immune activation.
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Authors | Hagir B Suliman, Karen E Welty-Wolf, Martha Sue Carraway, David A Schwartz, John W Hollingsworth, Claude A Piantadosi |
Journal | FASEB journal : official publication of the Federation of American Societies for Experimental Biology
(FASEB J)
Vol. 19
Issue 11
Pg. 1531-3
(Sep 2005)
ISSN: 1530-6860 [Electronic] United States |
PMID | 15994412
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Adaptor Proteins, Signal Transducing
- DNA, Mitochondrial
- Interleukin-6
- Intracellular Signaling Peptides and Proteins
- Myd88 protein, mouse
- Myeloid Differentiation Factor 88
- NF-kappa B
- RNA, Messenger
- Tlr2 protein, mouse
- Tlr4 protein, mouse
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Nitric Oxide Synthase Type II
- Interleukin-1 Receptor-Associated Kinases
- Protein Serine-Threonine Kinases
- Proto-Oncogene Proteins c-akt
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Topics |
- Adaptor Proteins, Signal Transducing
(metabolism)
- Animals
- DNA Damage
- DNA, Mitochondrial
(analysis, metabolism)
- Escherichia coli
(pathogenicity)
- Interleukin-1 Receptor-Associated Kinases
- Interleukin-6
(genetics)
- Intracellular Signaling Peptides and Proteins
(metabolism)
- Liver
(metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Mitochondria
(metabolism)
- Myeloid Differentiation Factor 88
- NF-kappa B
(metabolism)
- Nitric Oxide Synthase Type II
(antagonists & inhibitors, genetics)
- Oxidative Stress
- Protein Serine-Threonine Kinases
(metabolism)
- Proto-Oncogene Proteins c-akt
(metabolism)
- RNA, Messenger
(metabolism)
- Toll-Like Receptor 2
(analysis, physiology)
- Toll-Like Receptor 4
(analysis, physiology)
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